Production of soluble salts of



barbituri Patented July 2, 1935 UNITED STATES PATENTOF For certain isterbarbituric acids ample, for intravenous or rectal purposes, therelatively c acids themselves are unsuitable.

For such When so administer orally in the form of the 2,006,516 FlCE,

PRODUCTION OF SOLUBLE SALTS OF BARBITURIC ACIDS Donalee L. Tabern andNorman A. Hansen, Lake Bluff, 111., assignors to Abbott Laboratories,

North Chicago, 111., a corporation of Illinois No Drawing. ApplicationJune 2, 1932,

I Serial No. 615,025

13 Claims.

purposes, it is desirable to adminin soluble form, as, forexadministration. water-insoluble ed, the salts of barbituric barbituricacids.

It is known that 5,5-di-su'bstituted barbituric acids are soluble insolutions of alkali-metal hydroxides or alcoholates,

forming thereby the corresponding alkali-metal salts. However, thesolutions so prepared are unstable, there beingproturing standpoint,

technical disadvantages.

Anothermethod which has sists in preparing the salt of been suggestedconthe barbituric acid derivative in alcoholic or aqueous-alcoholicsolution and evaporating to the aqueous to dryness. -While superiormethod, it nevertheless is not entirely satisfactory because when somewater is present in the organic liquid, some hydrolysis of thebarbituric acid the product compound may also may occur, and becomediscolored and impure due to the fact that the solution is evaporatedcompletely to dryness.

We have discovered that all of the above disadvantages may be metal insolution, holate.

the acid, of the alcoholate, ity in the ketone,

acetone) and then adding the alkali because of the salts insolubilandmay be readily filtered off.

In another embodiment, where the acid has been dissolved in anseparated, after alcohol, the alkali salt may be addition of thealcoholate and consequent formation of the salt in solution, by

adding thereto a the alcohol.

The sodium salt of tive is thereby preci may be directly filter liquidhydrocarbon miscible in the barbituric acid derivapitated from solution,and ed off and dried.

as the ethyl ZJCO-r The salts are by both procedures obtained in anentirely pure, white, completely soluble condition. j

Thesalts so obtained have the general formu: la:

COVNX p in which R and R represent aliphatic, alicyclic, or aromaticgroups, and X represents an alkali metal, such as sodium, potassium, orlithium.

w EXAVMPLEVI a Sodium diethylbarbiturate To 185 grams diethylbarbituricacid dissolved in 750 cc. ethyl alcohol is added a solution of sodiumethylate prepared by dissolving 23 grams of sodium in 300 cc. ethylalcohol. To the solution so obtained is added 500 cc. benzene, whichcauses the sodium salt of diethylbarbituric acid to crystallize fromsolution in good yield. The salt is solves readily and completely inwater.

Instead of ethyl alcohol, methyl alcohol or acetone may be employed todissolve the diethylbarbituric acid in the above example, and the sodiummay be dissolved in another alcohol, such as methyl or propyl alcohoL.

EXAMPLE 2 Sodium phenyl ethyl barbiturate 23 grams sodium is dissolvedin 500 cc. absolute alcohol and the solution is filtered. In 800 cc.Warm absolute alcohol is dissolved 232 grams phenyl ethyl barbituricacid, and the solution is filtered. The two solutions are mixed, and 300cc. petroleum ether, hexalin or tetralin, is added. Sodium-phenyl ethylbarbiturate crystallizes from solution and is filtered off and dried.

EXAMPLE 3 Potassium salt of phenyl ethyl Ziarbituric acid Same method asExample 2, but using 39 grams potassium.

EXAMPLE 1- Sodium ethyZ-(I-methyl butyl) barbiturate 2 hydrocarbons suchas toluene, xylene, or petroleum ether,to bring about the precipitationof the pure salt.

7 EXAMPLE 5 Sodium ethyl- (1-methyl heptyl) barbiturate 23 grams sodiumTo this solution is added a solution of 269 grams of ethyl-(l-methylheptyl) barbituric acid in 800 cc. alcohol. To the mixed alcoholicsolution is added 1000 cc. benzene, which precipitates the sodium saltof the barbituric acid. The product is filtered and dried.

EXAMPLE 6 '7 Sodium ethyl-(leethyl propyl) barbiturate The sodium saltmay be prepared by a method similarto-thatgiven in Example 5.

EXAMPLE 7 Sodium ethyl secondary butyl barbiturate This sodium salt isprepared by the same methed as given in the preceding examples.

I ElK AMPI iE 8 Sodium diallyl barbiturate- The method of preparation isthe same as given in the preceding examples.

Exauru: 9 Sodium secormlar-y butylallyl barbiturate Same method as inpreceding examples. 0 V 'EXAMPIE 10 Lithium diethyl barbiturate V Sameas Example 1 butusing'l grams of lithium place Ofsodium. V V

V Exnnrm 11 Sodium ethyl cyclopentyl' barbiturate Same method as in"preceding examples.

7 EXAMPLE 12 V Sodium ethyl cycloheicertylbarbiturate Same method inpreceding examples.

V Exiurnn 13 Sodium ri-butjyl ethyl barbiturate Q 2.3 grams sodium isdissolved in 50cc. alcohol. 22 grams of n-butyli ethyl barbituric acidis dissolved in 100 cc. acetone. The separate solutions are filtered,then warmed slightly and mixed. Sodium n-ibutyl ethyl barbituratecrystallizes from solution as a white granular product completelysoluble in water'and alcohol.

The salts of barbituric acids so obtained are white, stable, readilywater-soluble compounds which are entirely suitable for therapeutic use.The 'salts vary in their solubility in' alcohol, butare'practicallyinsoluble in hydrocarbons and in ether'andacetone.

various modifications may doubtless be made in our inve'ntionwithoutdeparting from the, spirit thereof, and hence wed'o'notwish to belimited 'toithe specific procedure outlined or uses mentioned, but wishthe'scope of "our invention to be is dissolved in 300 cc. alcohol.

determined entirely from the appended claims, which are to beinterpreted as broadly as is consistent with the state of the art.

We claim as our invention:

1. A method of preparing in solid form an alkali-metal salt of I aformula-- o co in which R and R. represent aliphatic, alicyclic,

barbituric acid, adding to said solution an alkali barbituric acid ofthe metal inthe form of its alcoholate, and forming the alkali metalsalt of said acidasa precipitate of a relatively large proportion by thepresence of a liquid which it is insoluble, said liquid being a memberof the group consisting of inert alkyl' ketones and insert liquidhydrocarbons.

2. A method as defined in claim 1, wherein'said liquid is a solvent forsaid acid.

3. A method of preparing in solid form analkali-metal salt of abarbituric acid of the formulav I to K O-lL-X in which R and R" orphenyl radica and X represents an alkalimetal, which consistsindissolving the barbituri'c acid in an organic solvent whichis inertto'said barbituric acid andin which the alkali metal salts of said acidare insoluble, and adding to said solution'an alkali metal in the formofits alcoholate, whereby the alkali L to Lost... 7

inwhich R and R represent aliphatic, alicyclic, orphenyl radicals, and Xrepresents an "alkalimetal, which consists in forming the'salt of thebarbiturate insolutionin an inert organic solvent, and precipitating itfrom the solution by means of a liquid'hydrocarbon.

'7. A-methodof preparing an alkali-metal salt .ofabar-blturic acid of;the formulainwhichR and'Rf represent aliphatic, alicyclic,

or phenyl radicals, and K represents sodium,

represent aliphatic, alicyclic,

salt of'said acid-will be formed and will precipitate from said somwhich comprises forming the sodium salt in an inert organic solvent, andprecipitating it from the solution by means of a liquid hydrocarbon.

8. A method as described in claim 6, wherein R represents an ethylgroup, R represents aliphatic, alicyclic, or phenyl radical, and Xrepresents sodium.

9. A method as described in claim 6, in which R represents ethyl, Rrepresents the l-methyl butyl group, and X represents sodium.

10. A method as described in claim 6 in which the organic solvent isalcohol and in which the liquid hydrocarbon is benzene.

11. A method of preparing in solid form an alkali-metal salt of abarbituric acid of the formula in which R and R I 3 sodium salt ofethyl-(l-methyl-butyl) barbituric acid, having the formula /C OCHaCH2CHz-CH I l I CONNa OH:

which comprises forming said salt in alcoholic solution and addingthereto benzene to precipitate the salt.

13. A method of preparing in solid form the sodium salt ofethyl-(l-methyl-butyl) barbituric acid, having the formulawhich consistsin forming said salt in ethyl alcoholic solution and adding theretopetroleum ether to precipitate the salt.

CO-NNa DONALEE L. TABERN. NORMAN A. HANSEN.

CERTIFISATE 0F CORRECTIGN.

Patent No. 2, 6%, 630. July 2, 935.

DQNALEE L. TABERN, ET AL.

it is hereby ceftifiecl lilaafc error appears in the printedspecification of the above numbered patent requiring correctien aslallnws: Page 2, second column, line 24, claim 1, for "insart" readinert; fiIEiJl that the said Letters Patent should be read with thiscorrectinn therein that the sama may conform to the record of 116 casein the Patent Office.

Signed and sealed this 6th day of August, A. 1935.

Leslie Frazer (Seal) Acting Umnmissioner of Patents.

